The effect of 1% glucose loading on metabolism in the elderly patients during remifentanil-induced anesthesia: A randomized controlled trial

Previous studies showed that remifentanil-induced anesthesia can inhibit surgical stress response in non-diabetic adult patients and that low-dose glucose loading during anesthesia may attenuate fat catabolism. However, little is known about the influence of glucose loading on metabolism in elderly patients, whose condition may be influenced by decreased basal metabolism and increased insulin resistance.

R E S E A R C H A R T I C L E Open Access

The effect of 1% glucose loading on

metabolism in the elderly patients during

remifentanil-induced anesthesia: a

randomized controlled trial

Kohei Fukuta1* , Asuka Kasai1, Noriko Niki1, Yuki Ishikawa1, Ryosuke Kawanishi1, Nami Kakuta1, Yoko Sakai1, Yasuo M Tsutsumi2and Katsuya Tanaka1

Abstract

Background: Previous studies showed that remifentanil-induced anesthesia can inhibit surgical stress response in non-diabetic adult patients and that low-dose glucose loading during anesthesia may attenuate fat catabolism However, little is known about the influence of glucose loading on metabolism in elderly patients, whose condition may be influenced by decreased basal metabolism and increased insulin resistance We hypothesized that, in elderly patients, intraoperative low glucose infusion may attenuate the catabolism of fat without causing harmful hyperglycemia during remifentanil-induced anesthesia

Methods: Elderly, non-diabetic patients scheduled to undergo elective surgery were enrolled and randomized to receive no glucose (0G group) or low-dose glucose infusion (0.1 g/kg/hr for 1 h followed by 0.05 g/kg/hr for 1 h;

LG group) during surgery Glucose, adrenocorticotropic hormone (ACTH), 3-methylhistidine (3-MH), insulin, cortisol, free fatty acid (FFA), creatinine (Cr), and ketone body levels were measured pre-anesthesia, 1 h post-glucose

infusion, at the end of surgery, and on the following morning

Results: A total of 31 patients (aged 75–85) were included (0G, n = 16; LG, n = 15) ACTH levels during anesthesia decreased significantly in both groups In the LG group, glucose levels increased significantly after glucose loading but hyperglycemia was not observed During surgery, ketone bodies and FFA were significantly lower in the LG group than the 0G group There were no significant differences in insulin, Cr, 3-MH, and 3-MH/Cr between the two groups

Conclusion: Remifentanil-induced anesthesia inhibited surgical stress response in elderly patients Intraoperative low-dose glucose infusion attenuated catabolism of fat without inducing hyperglycemia

Trial registration: This study has been registered with the University hospital Medical Information Network Center (http://www.umin.ac.jp/english/) Trial registration number:UMIN000016189 The initial registration date: January 12th 2015

Keywords: Glucose, Metabolism, Elderly, Remifentanil

© The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the

* Correspondence: kouhei_f_1983@yahoo.co.jp

1 Department of Anesthesiology, Graduate School of Biomedical Sciences,

Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, Japan

Full list of author information is available at the end of the article

Glucose tolerance is decreased during surgery by

catechol-amines and stress hormones, such as cortisol and

adreno-corticotropic hormone (ACTH) [1–4], and intraoperative

hyperglycemia is a risk factor for postoperative

complica-tions and mortality [5–7] Therefore, glucose solution is

not generally infused during surgery, despite the fact that

an energy deficit may lead to the catabolism of fats and/or

proteins Several studies show that remifentanil reduces

the stress response during surgery [8–11] We previously

reported that anesthesia using remifentanil limits the

sur-gical stress response in non-diabetic adult patients and

that low-dose glucose loading during anesthesia may

at-tenuate the catabolism of fat [12] Sawada et al also

showed that intraoperative glucose infusion suppressed

lipolysis and proteolysis in patients anesthetized with

remifentanil [13]

It is reported that basal energy expenditure (EE) is

negatively associated with age in subjects > 52 years old

[14] In addition, many studies have reported that insulin

secretion decreasing and resistance increasing with age

[15–18] Elderly patients are, therefore, influenced by a

decrease in basal metabolism and an increase in insulin

resistance These studies suggest that, while low-dose

glucose loading during remifentanil-induced anesthesia

may decrease stress hormone secretion and fat

catabol-ism without causing hyperglycemia in adults, it may

in-duce hyperglycemia in elderly patients Currently, little

is known about the effect of glucose loading on

metabol-ism in elderly patients during remifentanil-induced

anesthesia

Here, we hypothesized that, in elderly patients,

intra-operative low glucose infusion during

remifentanil-induced anesthesia may attenuate the catabolism of fat

without causing harmful hyperglycemia To test this

hy-pothesis, we examined the effects of glucose infusion on

metabolism in elderly patients anesthetized with

remifentanil

Methods

Study design and patient selection

Elderly (aged 75–85 years), non-diabetic patients

scheduled to undergo elective surgery in the

Tokush-ima University Hospital between September 2015 and

September 2016 were enrolled Patients were required

to have an American Society of Anesthesiologists

physical status of 1 or 2 and a scheduled surgery

dur-ation of > 1 h Obese (body mass index [BMI] > 30 kg/m2)

and emaciated (BMI < 17 kg/m2) patients were excluded,

as were those taking steroids or diagnosed with diabetes

or thyroid disease Patients requiring the use of a

tourni-quet or laparoscopy during surgery were also excluded

from the final analysis Homeostasis Model Assessment

Insulin Resistance (HOMA-IR) was calculated by the

formula: fasting insulin [μIU/ml] × fasting glucose [mg/dl] / 405 Eligible patients were randomized to receive no glu-cose (0G group) or a low-dose gluglu-cose infusion (0.1 g/kg/

hr for 1 h followed by 0.05 g/kg/hr.; LG group) during surgery

The study was approved by Clinical Trial Center For Developmental Therapeutics of the Tokushima Univer-sity Hospital, and the reference number was 2211–1 All participating subjects provided written informed con-sent The study was registered with the University hos-pital Medical Information Network Center (http://www umin.ac.jp/english/); ID: UMIN000016189

Anesthesia management and study protocol

Patients were allowed to eat until 00:00 h on the day of surgery Patients scheduled for surgery in the morning received 250 ml (200 kcal) of Arginaid Water® (Nestle Japan Ltd., Tokyo, Japan), and those scheduled in the afternoon received 500 ml (400 kcal) 2 h before anesthesia The nutrient profiles of Arginaid Water® are shown in Table1 No patients were premedicated

On arrival in the operating room, a 20 G catheter was inserted into the forearm of each patient and bicarbon-ate Ringer’s solution without glucose was infused Gen-eral anesthesia was induced by intravenous administration of thiamylal (3 mg/kg) and remifentanil (0.25–0.5 μg/kg/min), and maintained with sevoflurane (end-tidal sevoflurane ≥1.0%) and remifentanil (0.2– 0.5μg/kg/min) Muscle relaxation with 0.7 mg/kg rocur-onium bromide was performed to facilitate tracheal in-tubation Rocuronium bromide was administered intermittently, if required All patients were maintenance

of the BIS value between 40 to 60 during the surgery The study protocol is illustrated in Fig 1 After tra-cheal intubation, the heat and moisture exchange filter was equipped with an S/5 compact monitor (GE Health-care, Helsinki, Finland) The tidal volume was set at 7 ml/kg, the respiratory rate set with the aim of normo-capnia, and the O2/air mixture at FiO2 0.5 Stable data

Table 1 Major nutrients in Arginaid Water®

Nutrients Arginaid water 100 mL Calories (kcal) 80

Moisture (g) 85.6 Arginine (g) 2.0

Sodium (mg) 0 Phosphate (mg) 140 Zinc (mg) 0.8 Copper (mg) 0.8

for respiratory quotient (RQ), oxygen consumption ( ˙V

O2), carbon dioxide output ( ˙V CO2), and EE were

ob-tained from the S/5 compact monitor within

approxi-mately 20 min (time 0) In the LG group, the solution

was switched to 1% glucose acetated Ringer’s solution at

time 0, with the solution for both groups being initiated

at 10 ml/kg/hr for 1 h, followed by 5 ml/kg/hr

There-fore, in the LG group, glucose was taken at 0.1 g/kg/hr

for 1 h, followed by 0.05 g/kg/hr

Measurements

Blood was sampled at baseline (introduction of

anesthesia), 1 h after time 0, at the end of surgery, and

the next morning Glucose concentrations were

mea-sured using a blood glucose monitor (Medisafe Fit,

TERUMO, Tokyo, Japan) Blood glucose concentrations

> 200 mg/dl were defined as hyperglycemia in this

study Patients with blood glucose concentrations >

250 mg/dl were intravenously injected with 2 U insulin

Blood samples were centrifuged at 150 g at 4 °C for 10

min (Table Top cooling centrifuge 2800, Kubota,

Tokyo, Japan), and plasma and serum samples were

stored at − 20 °C until analysis Plasma concentrations

of glucose, ACTH, and 3-methylhistidine (3-MH) and

serum concentrations of insulin, cortisol, free fatty acid

(FFA), creatinine (Cr), and ketone bodies were

ana-lyzed Plasma glucose was measured using the

hexokinase method, plasma ACTH by an electro chemiluminescent immunoassay, and plasma 3-MH by high-performance liquid chromatography Serum con-centrations of FFA, ketone bodies, and Cr were mea-sured enzymatically, serum insulin by a chemiluminescent enzyme immunoassay, and serum cortisol by a radioimmunoassay RQ, ˙V O2, ˙V CO2, and

EE were measured by the S/5 compact monitor and re-corded at 30 min intervals until the end of surgery

Randomization and blinding

We used a computer-generated distribution (Quick-Calcs, GraphPad Inc., La Jolla, CA, USA) for ran-domly allocation Anesthesiologists collecting intraoperative data were not blinded to group assign-ment, however, patients, surgeons and another anesthesiologist evaluating the date were blinded to group assignment

Endpoints

The primary endpoint in the present study was the con-centration of FFA Secondary endpoints included the concentration of ketone bodies (i.e lipid metabolism), the value of 3MH/Cr (i.e protein catabolism), glucose and serum insulin concentrations (i.e glucose metabol-ism), ACTH and serum cortisol concentrations (i.e

Fig 1 Study protocol EE, energy expenditure; RQ, respiratory quotient; TV, tidal volume; RR, respiratory rate

stress hormone), and RQ (i.e the energy source that they

used)

Statistical analysis

The primary endpoint was the concentration of FFA

Our previous study reported that the concentration of

FFA in adult patients at 2 h after the initiation of

infu-sion was significantly higher in patients who received no

intraoperative glucose than in those who received 1%

glucose intraoperatively (840 ± 290 versus 510 ± 240

μEq/L, respectively) [12] Anticipating that the mean

dif-ference between the groups during surgery would be

330 ± 260 μEq/L, the minimum number of patients in

each group was 12, with an alpha of 0.05 and a power of

80% for FFA We estimated that 32 patients should be

included in this trial, with 16 patients in each group,

be-cause of possible dropouts and complications during

surgery

The Shapiro–Wilk test for fit with normal distribution

was performed In parametric data, differences between

the time points within each group were compared using

repeated-measures analysis of variance with the

Bonfer-roni post hoc test Parametric data at the same time

points between the two groups of variables were

ana-lyzed by unpaired t-tests In nonparametric data,

differ-ences between the time points within each group were

compared using Friedman’s test Nonparametric data at

the same time points between the two groups of

vari-ables were analyzed by the Mann–Whitney rank-sum

test Nominal scales were analyzed by the Chi-squared test P < 0.05 was considered to be statistically signifi-cant All statistical analyses were performed with SPSS version 20 (IBM, New York, NY, USA)

Results

Patient recruitment and flow through the protocol is summarized in Fig 2 Although 34 patients were en-rolled, one was excluded due to undiagnosed diabetes and one patient refused to participate Thirty-two pa-tients were randomized to the 0G and LG groups; one patient in the LG group was excluded from the analysis

as a non-permitted fluid was administered to treat bleed-ing Therefore, 31 patients completed the trial and were included in the analysis The patients’ demographic data and surgical procedures are shown in Tables 2 and 3

No notable differences were seen between the 0G and

LG groups

Levels of ACTH and cortisol at each study timepoint are shown in Fig 3 ACTH levels during surgery were significantly lower than baseline in both groups (Fig.3a)

As shown in Fig 4a, plasma glucose levels in the LG group were significantly higher than those in the 0G group at 1 h (P = 0.006) At 1 h and at the end of sur-gery, plasma glucose levels were significantly higher than baseline levels in the LG group (1 h vs baseline: P < 0.001, the end of surgery vs baseline: P = 0.043) How-ever, the highest glucose concentration in the LG group was 156 mg/dl and none of the patients in either group

Fig 2 Study flow diagram

required intravenous insulin or experienced

hypoglycemia (< 70 mg/dl)

FFA levels in the LG group were significantly lower

than those seen in the 0G group at 1 h and the end of

surgery (1 h: P = 0.004, the end of surgery: P = 0.001;

Fig 5a) Levels of ketone bodies in the LG group were

significantly lower than those in the 0G group at 1 h and

at the end of surgery (1 h:P = 0.037, the end of surgery:

P = 0.007; Fig 5b) Levels of ketone bodies at 1 h were

significantly higher than those at baseline in the 0G

group (P = 0.02; Fig.5b)

There were no significant differences between the two

groups in EE (Fig.6a), RQ (Fig.6b), ˙V O2, ˙V CO2,

insu-lin (Fig.4b), Cr, 3-MH, and 3-MH/Cr

Discussion

In this study of elderly patients, FFA levels in the LG

group were significantly lower than those in the 0G

group at 1 h and at the end of surgery Levels of ketone

bodies in the LG group were significantly lower than those seen in the 0G group at 1 h and the completion of surgery In addition, levels at 1 h were significantly higher than those seen at baseline in the 0G group These results indicate that 1% glucose loading during remifentanil-induced anesthesia attenuated the catabol-ism of fat in this patient group

Our previous study of adult patients demonstrated that ketone levels in subjects with no glucose loading were approximately 300μmol/L during surgery [12], whereas in the current study of elderly patients, ketone body levels were approximately 500μmol/L in the 0G group However, in both studies, ketone body levels dur-ing surgery were approximately 200μmol/L in the LG group This observation suggests that low-dose glucose loading may be more effective in elderly patients than in adult patients as a whole

In the present study, all patients were given Arginaid Water® 2 h before anesthesia Arginaid Water® are carbo-hydrate with aminoacid solution, and the nutrient pro-files are shown in Table 1 In our previous study, we investigated whether the intake of preoperative carbohy-drate with aminoacid solution can improve starvation status and lipid catabolism before the induction of anesthesia, and reported that the intake of preoperative carbohydrate with aminoacid solution significantly de-crease FFA and ketone bodies at the initiation of anesthesia compared with the control group [19] There-fore, non-preoperative Arginaid Water® may cause more significantly difference in FFA and ketone bodies be-tween 0G group and LG group

HOMA-IR has been used widely to measure insulin sensitivity and resistance based on fasting plasma glu-cose and insulin concentrations [20, 21] Esteghamati A

et al reported that the 75th percentile of HOMA-IR was 1.6 in heaIthy Iranians [22] Beak JH et al reported that the overall optimal cut-off value of HOMA-IR for identi-fying dysglycemia was 1.6 in both sex, and that the cut-off values for type 2 diabetes mellitus were 2.87 in men and 2.36 in women [23] Ascaso JF et al reported that the 75th percentile value as the cut-off point to define insulin resistance corresponded with a HOMA-IR of 2.6 [24] In the present study, HOMA-IR did not differ sig-nificantly between the two groups (0G group: 1.85 ± 0.95, LG group: 1.61 ± 0.94,P = 0.40; Table2) The high-est HOMA-IR in the 0G group was 4.0, and that in the

LG group was 4.2 Therefore, in the present study, insu-lin resistance were increased in both groups

In the present study, no significant changes in insulin levels were seen However, our previous study of adult patients showed a significant increase in insulin levels after low-dose glucose loading during surgery [12] Many studies have reported that insulin secretion decreasing and resistance increasing with age [15–18] Lozzo et al

Table 2 Demographic data

0G group LG group P value Male/Female 4/12 7/8 P = 0.21

Age (yr) 78.5 ± 2.8 79.0 ± 4.0 P = 0.83

Height (cm) 151.0 ± 6.3 157.7 ± 7.6 P = 1.0

Weight (kg) 57.3 ± 6.7 58.8 ± 13.1 P = 0.70

BMI (kg/m2) 24.0 ± 2.0 24.2 ± 3.1 P = 0.81

HOMA-IR 1.85 ± 0.95 1.61 ± 0.94 P = 0.40

APACHE II score 8 ± 4 7 ± 2 P = 4.23

Operation time (min) 101.5 ± 35.9 142.0 ± 69.4 P = 0.06

Blood loss (ml) 50.0 ± 47.1 90.0 ± 267.5 P = 0.57

Data are expressed as the mean ± SD

There were no statistically significant differences between the 2 groups

Table 3 Types of surgical procedure performed

0G group LG group

Cervical laminoplasty 3 Cervical laminoplasty 1

Lumbar partial laminectomy 1 Microendscopic lunbar

laminectomy

1 Discectomy 1 Lumbar posterior fusion 3

Total hip arthroplasty 2 Extreme lateraI interbody fusion 1

Mastectomy 3 Total hip arthroplasty 1

Skin malignant tumor resection 1 Mastectomy 1

Scar plasty 1 Patial mastectomy 1

Laryngomicrosurgery 1 Flap surgery 1

Dacryocystorhinostomy 1 Laryngomicrosurgery 1

Perineoplasty 1 Endoscopic sinus surgery 1

Adnexectomy+colpoplasty 1 Dacryocystorhinostomy 1

Tension-free vaginal tape 1 Closure of colostomy 1

investigated basal β-cell function in 957 non-diabetic

European patients aged 18–85 years, reporting that aging

is associated with decreased basal insulin release [15]

Muzumdar et al studied insulin secretion in rats aged

3–20 months, showing that glucose-stimulated insulin

secretion decreased with age in this in vivo model [16]

Reaven et al studied glucose-stimulated insulin release

in β-cells of 2–18-month-old rats, demonstrating that

the aging process leads to defects in glucose-stimulated

insulin release from β-cells [25] Therefore, the results

seen in our current and previous studies support the

data obtained by other groups indicating that aging is

as-sociated with impaired glucose-stimulated insulin

release

Parsons et al reported that acute hyperglycemia

ad-versely affects stroke outcome [26] In the present study,

plasma glucose levels were higher in the LG group than

in the 0G group at 1 h and higher at 1 h and at the end

of surgery than at baseline in the LG group However, as the highest concentration of glucose in both groups was

156 mg/dl, none of the patients required intravenous in-sulin These results suggest that, even in elderly patients, remifentanil-induced anesthesia may prevent hypergly-cemia associated with low-dose glucose infusion

Remifentanil-induced anesthesia decreases stress hor-mones, such as ACTH and cortisol, and suppresses the surgical stress response in adults [8–11] Demirbilek

et al compared the effects of remifentanil and alfentanil

as part of total intravenous anesthesia on plasma con-centrations of cortisol, insulin, and glucose in patients undergoing abdominal hysterectomy, demonstrating that remifentanil-induced anesthesia was associated with de-creased cortisol levels [8] We previously reported that anesthesia using remifentanil significantly decreases

Fig 3 Plasma ACTH (a) and serum cortisol (b) concentrations in the 0G and LG groups prior to induction of anesthesia (base), at 1 h (1H) from time 0, at the end of surgery (end), and on the next morning (next) * P < 0.05 versus baseline; #P < 0.05 between groups

Fig 4 Plasma glucose (a) and serum insulin (b) concentrations in the 0G and LG groups prior to induction of anesthesia (base), at 1 h (1H) from time 0, at the end of surgery (end), and on the next morning (next) * P < 0.05 versus baseline; #P < 0.05 between groups

ACTH and cortisol levels in adult patients [12] In the

present study, ACTH in both the 0G and LG groups was

significantly decreased during remifentanil-induced

anesthesia, suggesting that general anesthesia using

remifentanil may suppress the stress response in elderly

patients

There were no significant differences in 3-MH/Cre

levels in our current or previous studies [12] In the

present study, the surgical procedures were primarily

performed on the body surface, rather than being highly

invasive, and the surgery time was approximately 2 h

The aim was to exclude the influence of surgical stress

in order to observe the effect of aging in the present

study Sawada et al showed that 3-MH/Cr levels at 6 h

were significantly higher than levels prior to anesthesia

during major surgery in patients receiving no glucose

infusion [13] This discrepancy suggests that significant surgical stress may induce protein catabolism in the ab-sence of glucose loading

In the present study, subjects were elderly, but were not obese It is reported that age per se does not increase HOMA-IR levels and that the changes might be related

to higher rates of obesity in older subjects [27] In addition, it is reported that the deterioration of glucose tolerance in healthy elderly subjects is due to a decrease

in insulin secretion and can be explained by the degree

of obesity rather than age [28] Furthermore, one study demonstrated that aging has no effect on insulin sensi-tivity independent of changes in body composition [29] These studies show that age itself does not increase in-sulin resistance and that changes may be related to the development of obesity The low-dose glucose infusion

Fig 5 Serum FFA (a) and ketone body (b) concentrations in the 0G and LG groups prior to induction of anesthesia (base), at 1 h (1H) from time

0, at the end of surgery (end), and on the next morning (next) * P < 0.05 versus baseline; #P < 0.05 between groups

Fig 6 EE (a) and RQ (b) in the 0G and LG groups from the time of stabilization (time 0) to the end of surgery (end) EE, energy expenditure; RQ, respiratory quotient

during remifentanil-induced anesthesia in obese patients

may, therefore, induce hyperglycemia In the present

study, one patient whose BMI was > 30 kg/m2 was

ex-cluded and BMI did not differ significantly between the

two groups (0G group: 24.0 ± 2.0 kg/m2, LG group:

24.2 ± 3.1 kg/m2, P = 0.81; Table2) The highest BMI in

the 0G group was 26.9 kg/m2, and that in the LG group

was 29.1 kg/m2 While further studies are required to

evaluate this association further, in the current study of

elderly, non-obese patients, low-dose glucose loading

during remifentanil-induced anesthesia attenuated fat

catabolism without causing hyperglycemia

Acute Physiology and Chronic Health Evaluation

(APACHE) II score is a general measure of severity of

disease, has been used to predict hospital mortality [30–

32] We have done analysis to evaluate APACHE II score

with preoperative data Gupta S et al reported that

crit-ically ill patients (CIP) with APACHE II score of≥15 at

admission or within 24 h are at risk for the development

of CIP [31] Joe BH et al reported that patients with

APACHE II score greater than 20 had tendency to

ex-pire than the others, and that APACHE II score more

than 20, rather than cardiac function, is associated with

mortality in patients with stress-induced cardiomyopathy

[32] In present study, APACHE II score did not differ

significantly between the two groups (0G group: 8 ± 4,

LG group: 7 ± 2, P = 4.23; Table 2) The highest

APA-CHE II score in the 0G group was 12, and that in the

LG group was 11 In present study, elderly (75–85 years)

were required to have American Society of

Anesthesiolo-gists physical status of 1 or 2 Therefore, in present

study, there were low severity in both groups

In the present study, we used sevoflurane, but not

pro-pofol, to maintain the general anesthesia in elderly

pa-tients Sevoflurane and propofol are commonly used

general anesthetics during surgery Several clinical

stud-ies were tried to see whether the choice of the anesthetic

agent make a difference in postoperative delirium or the

postoperative cognitive dysfunction (POCD) after

non-cardiac surgery in elderly patients Some studies

indi-cated that propofol reduced POCD as compared with

sevoflurane [33, 34] In contrast, it was reported that

propofol significantly increased the delirium rating scale

on day 2 and 3 after surgery, the time required for

emer-gence from anesthesia as defined by eye opening and the

time to tracheal extubation, as compared with

sevoflur-ane [35] Recent systematic review reported that it was

uncertain whether maintenance with propofol or with

volatile anesthetics affect incidence of postoperative

de-lirium, mortality, or length hospital stay as certainty of

the evidence was very low [36] Additionally, the authors

showed low-certainty evidence that maintenance with

propofol may reduce POCD [36] Thus, there is

insuffi-cient evidence to inform the choice of general anesthetic

agent with respect to the beneficial effect during surgery

in the elderly patients

It was well known that volatile anesthetics were able

to impair insulin secretion and glucose utilization [37] Our previous studies using patch clamp experiments and intravenous glucose tolerance tests in rabbits indi-cated that isoflurane-induced inhibition of insulin secre-tion was mediated by the isoflurane-induced opening of adenosine triphosphate-sensitive potassium (KATP) chan-nels in pancreatic β-cells, while propofol had no effects

on the KATPchannels in pancreaticβ-cells, consequently

no inhibition of insulin secretion [38, 39] It is also re-ported that sevoflurane reduced glucose tolerance com-pared with propofol [40] In the present study, we showed in the elderly patients that low-dose glucose load was able to be safe during sevoflurane based anesthesia These results suggest that low-dose glucose load may be safe during propofol based anesthesia as well

There were no significant differences in EE and RQ data in the current study of elderly patients or our previ-ous study of adult subjects [12] The low-dose glucose load may, therefore, not influence EE and RQ, although these parameters may change in patients undergoing major surgery

This study has several limitations First, data were ob-tained over a relatively short period, the final timepoint being the morning of postoperative day 1 Although we did not investigate the influence of glucose on long-term outcomes, there were no significant differences in pro-tein catabolism Second, in present study, the surgeries were minor surgery, because we want to exclude the in-fluence of surgical stress to see the effect of aging on lipid metabolism in the present study There may be sig-nificantly difference in prolonged and major surgery Further studies to see the differences of low-dose glu-cose loading on the lipid metabolism and protein catab-olism in the prolonged and major surgery are needed However, we demonstrated that even in minor surgery with a little stress, low-dose glucose loading to the eld-erly patients improved lipid metabolism without devel-oping hyperglycemia Prolonged and major surgery in the absence of glucose loading was shown to induce pro-tein catabolism in adults [13] These results suggest that

in major surgeries and/or prolonged surgeries which in-duce more remarkable stress, low-dose glucose loading

to the elderly patients may control the increase of FFA and the ketone bodies and inhibit protein catabolism, when compared without glucose loading Third, there were differences in the types of surgical procedures per-formed on patients in the two groups These differences, however, were regarded as irrelevant because the con-centrations of ACTH and cortisol during surgery were similar in the two groups Finally, in the present study, the elderly patients who were not diabetes were subject

of the study The effects of low dose glucose infusion on

both glucose and fat metabolism on elderly patients with

diabetes or acute neurologic insults are not clear from

the findings of the present study

Conclusions

The present study indicates that intraoperative low

glu-cose infusion during remifentanil-induced anesthesia

at-tenuated the catabolism of fat without causing harmful

hyperglycemia in this population of elderly patients

These data suggest that low-dose glucose loading may

be useful in elderly patients undergoing relatively minor

surgical procedures

Abbreviations

3-MH: 3-methylhistidine; ACTH: adrenocorticotropic hormone; Cr: creatinine;

EE: energy expenditure; FFA: free fatty acid; HOMA-IR: Homeostasis Model

Assessment Insulin Resistance; RQ: respiratory quotient; ˙VO 2 : oxygen

consumption; ˙VCO2: carbon dioxide output

Acknowledgments

Not applicable.

Authors ’ contributions

KF collected date, performed the statistical analysis, and write the

manuscript AK collected date and performed the statistical analysis NN

designed the study and collected date YI, RK, YS, NK and YMT collected

date KT designed the study, helped the statistical analysis and edited the

manuscript All author read and approved the final manuscript.

Funding

No extaernal funding source was used.

Availability of data and materials

The date and materials are available from the corresponding author upon

reasonable request.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the Tokushima

University Hospital All participating subjects was informed about this study

protocol in details and provided written informed consent before enrollment

in this study.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Author details

1 Department of Anesthesiology, Graduate School of Biomedical Sciences,

Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.

2 Department of Anesthesiology and Critical Care, Graduate School of

Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi Minami,

Hiroshima 774-8551, Japan.

Received: 7 March 2019 Accepted: 28 May 2020

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